Decreased Norepinephrine Content in the Medulla Oblongata in Severely Hypertensive Rats

Takami, Takeshi; Ito, Hiroyuki; Suzuki, Tsuneyuki

doi:10.1111/j.1440-1681.1993.tb01664.x

Cited by 8 publications

(7 citation statements)

References 16 publications

(16 reference statements)

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“…Takami and co‐workers found that in young, mature (10 weeks) severely hypertensive stroke‐prone SHR, the tissue level of NA in the medulla oblongata was significantly lower than in the control strain WKY rat (Takami et al 1993). Similar observations were reported by others and, interestingly, the medulla oblongata was the only brain region where a decrease in NA in the SHR was significant (S143).…”

mentioning

confidence: 99%

Altered central catecholaminergic transmission and cardiovascular disease

Kasparov

Teschemacher

2008

Experimental Physiology

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Numerous studies, some of which date back more than three decades, have established a link between disorders of the cardiovascular system and the catecholaminergic system of the brain. Central noradrenergic (and putative adrenergic) neurones are involved in numerous brain functions, and there appears to be more than one mechanism via which a dysfunction of central nor/adrenergic signalling may be detrimental to the cardiovascular system. Moreover, in some cases, such as essential hypertension, altered noradrenergic transmission could play a causative role. Numerous controversies are evident throughout the literature, which are very difficult to explain without much better understanding of the basic physiology of central noradrenergic transmission. Recently, using a combination of novel molecular, electrochemical and imaging techniques, we have started to unravel how noradrenergic neurones in the brain store and release their transmitter. Targeted long-term modulation of specific noradrenergic cell groups in defined brain areas using viral gene transfer is helping to clarify the links between central catecholamines and cardiovascular control in health and disease. These studies may reveal new therapeutic strategies for various cardiovascular diseases which are accompanied by heightened sympathetic nerve activity.

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confidence: 99%

Altered central catecholaminergic transmission and cardiovascular disease

Kasparov

Teschemacher

2008

Experimental Physiology

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“…These results suggested "…that lower Dbh in the young SHR presents a 'bottleneck' in catecholamine biosynthesis, leading to dopamine accumulation and catecholamine depletion in adrenergic cells, which then contributes to the pathogenesis of hypertension" (Jirout et al 2010). It has been suggested that reduced DBH activity in the brain leads to higher dopamine and lower norepinephrine levels which might represent a possible mechanism connecting reduced central DBH activity with increased blood pressure (Howes et al 1984, Cornish et al 1997, Takami et al 1993. However, in our previous studies, we did not determine Dbh expression levels or catecholamine levels in the brainstem (Jirout et al 2010).…”

Section: Introductionmentioning

confidence: 65%

Effects of Transgenic Expression of Dopamine Beta Hydroxylase (Dbh) Gene on Blood Pressure in Spontaneously Hypertensive Rats

Pravenec

Landa²,

Zidek³

et al. 2016

Physiol Res

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The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model.

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“…1C), likely leading to impaired or reduced ability of SHR to store catecholamines in this brain region vital to BP regulation. In fact, it was previously shown that the norepinephrine content was decreased in the NTS (in the medulla oblongata of the brainstem) of SHR versus WKY (28), and in the medulla oblongata (brainstem) of SHRSP versus WKY (29).…”

Section: Central Versus Peripheral Expression Of Chromogranin Amentioning

confidence: 94%

“…We are not the first to hypothesize involvement of the brainstem in the pathogenesis of hypertension in the SHR. Takami et al (29) hypothesized that since norepinephrine was decreased in the NTS in the medulla oblongata of SHR, and since norepinephrine has an inhibitory effect in the NTS on systemic BP elevation, 'the suppression of negative feedback due to a decrease in the activity of inhibitory neurons in the medulla oblongata appears to be involved in the development and progression' of hypertension in the SHR (29); we build upon the conclusions of Takami et al (29) to include a genetic basis at the Chga locus.…”

Section: Chga As a Contributor To The Pathogenesis Of Hypertension Inmentioning

confidence: 99%

MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension

Friese

Altshuler

Zhang³

et al. 2013

Human Molecular Genetics

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Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar-Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3'-untranslated region (3'-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis-quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3'-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3'-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (∼18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension.

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Decreased Norepinephrine Content in the Medulla Oblongata in Severely Hypertensive Rats

Cited by 8 publications

References 16 publications

Altered central catecholaminergic transmission and cardiovascular disease

Altered central catecholaminergic transmission and cardiovascular disease

Effects of Transgenic Expression of Dopamine Beta Hydroxylase (Dbh) Gene on Blood Pressure in Spontaneously Hypertensive Rats

MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension

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